The aim of this study is to characterize the effects of phorbol esters (PC) and other tumor promoters on mammalian development, and to attempt to modify these effects using anti-promoting agents. A thorough understanding of the actions of promoters and anti-promoters is necessary if manipulation of promotion is to be a fruitful approach to cancer prevention. The experiments will provide information of relevance to three areas of interest:(1) The theory that an important first step in promotion is dedifferentiation and induction of embryonic-like cells (stage 1) which are sensitive to subsequent PE actions (stage 2). (2) The hypothesis that PE's and transforming growth factors (TGF) act by similar mechanisms and that TGF's are normal components of embryogenesis. (3) Our proposal that there is overlap between the processes of promotion and teratogenesis. To establish if promoters can affect embryonic development in vivo, rodents at various stages of gestation will be treated with 12-0-tetradecanoylphorbol-13-acetate (TPA), 4-0-Methyl TPA (weak stage 1 promoter) or mezerein (MZ, stage 2 promoter). Fetal growth and morphology will be examined at term. To examine the direct effects of tumor promoters on development, we will use rodent conceptuses and limb-buds in culture. TPA actions on growth and differentation will be characterized, followed by structure-activity studies with other PE's. we will also study the effects of MZ and the modifying actions of fluocinolone acetonide, retinoic acid, protease inhibitors andsuperoxide dismutase on PE and MZ effects. In addition we will measure ornithine decarboxylase, sister chromatid exchanges and specific PE binding in susceptible and resistant embryo tissues. To establish if developmental effects are limited to diterpenes, we will also study the actions of anthralin and 2 bile acids. Preliminary studies justify pursuit of these objectives. Treatment of CD-1 mice with TPA is teratogenic, particularly for renal development, and at certain stages of gestation, embryolethal. The development of rat conceptuses in vitro is disrupted by nMolar concentrations of TPA with phorbol 12,13 diacetate and 4-0-MeTPA being 170 and 1400 fold less potent, respectively. The effect is restricted to a specific embryonic age and the action of TPA is inhibited by a non-filterable component of adult rat serum.